Fragile X (FRAX) is the most common known inherited cause of neurodevelopmental disability, resulting from a disruption in expression of the fragile X mental retardation 1 gene (FMRI). Associated with increased risk for a particular profile of cognitive deficits (including mental retardation) and a number of aberrant behaviors (including attentional dysfunction, hyperactivity, perseveration, stereotypies, hyperarousal and social deficits), this life long condition results in considerable impairment to individuals and confers a substantial burden on families and society. A series of cross-sectional neuroimaging studies of older children and adults, from our collaborative group of investigators, demonstrate an association between reduced FMR1 function and a pattern of brain abnormalities in the frontal, striatal, parietal, cerebellar and temporal lobe (hippocampus and superior temporal gyrus) regions. Further, these brain abnormalities are associated with selected cognitive and behavioral abnormalities that are characteristic of FRAX (e.g., enlarged caudate and stereotyped behavior and hyperactivity). In this Collaborative R01, between Stanford (PI: Allan Reiss) and UNC-Duke (PI: Joe Piven), we propose to conduct a longitudinal MM study of 60 FRAX, 60 developmentally-delayed (DD) and 30 typically-developing (TYP) males at age 18-42 months and again 24 months later at age 42-66 months. The overarching aim of this application is to examine the trajectory of gene, brain and behavior relationships, from a developmental perspective, beginning at the earliest ages that it is feasible to undertake such a study (in the three proposed study groups). We believe that this study requires a collaborative effort to: (1) insure a sufficient sample size for study and, (2) to combine a wide range of necessary and complementary expertise and experience. We have assembled a unique team of investigators, experienced in longitudinal behavioral studies of very young children with FRAX, neuroimaging of FRAX and autism, multi-site neuroimaging studies and advanced methods of image processing, that we believe is ideally suited to conduct this study. FRAX offers an important model for understanding the developmental relationships between a complex pattern of cognitive and behavioral abnormalities, brain structure and function, and gene function. Further study of this model system is likely to provide important insights into the pathogenesis and treatment of FRAX and other developmental disorders and abnormalities of behavior and cognition.